6, 16-dialkyl-17-oxygenated steroids



3,085,090 6,16-DIALKYL-17-0XYGENATED STEROIDS Robert P. Graber and Martin B. Meyers, Minneapolis,

Minn., assignors to General Mills, Inc., a corporation 5 of Delaware No Drawing. Filed Mar. 17, 1961, Ser. No. 96,372 18 Claims. (Cl. 260-239.55)

gesterones are unusually active progestational hormones 15 in themselves and are useful as intermediates for further conversion to other progestogens or to cortical hormones.

The invention can best be followed by means of the following schematic representation in which R and R' are alkyl groups having from 1 to 8 carbon atoms and R and- R may be the same or different alkyl groups and the acyl group may take the form where R' is an alkyl, cycloalkyl, aralkyl or alkoxyaralkyl group, the alkyl group generally having from 1 to 12 carbon atoms and the aryl group generally being phenyl. Illustrative of such ester groups are the acetate, caproate, cyclopentyl propionates, phenyl propionate, p-propoxyphenyl propionate, p-hexoxyphenyl propionate and pdodecoxyphenylpropionate. Since the activity of the compound varies dependent on the acylate group in the 17 position, the acylate group in this position may be varied widely to provide the activity desired. As the particular acylate group in positions 3 and 21 have little if any efiect on the activity, the acylate groups in this position will generally be those where R is an alkyl group having from 1 to 12 carbon atoms. 7

CH3 CH| CH3 11.0 I O 11.0 11.0

---OH --OH "OH R! R! R! H10 H30 H30 HO 0 O:

I g v 5 VI VII R R0 R R OH OH 1 --O-Acyl -R VIII Briefly, the synthetic route described above leads by way of novel intermediates to a series of novel dialkyl-l7- 1 0H, oxygenated progesterones of potent biological activity as H G J H o 5 oral progestational agents. The starting material for this I L0 synthesis is a 6-alkyl-16-dehydroprogenenolone either as such or as a 3-ester derivative. The 16-alkyl group and Hag H O the 17-oxygen function are first introduced by way of A V Grignard alkylation, which is then followed by enol acyla- I tion, epoxidation and hydrolysis. If 6-alkyl-16-dehydro- 40 pregnenolone itself is employed as the starting material, R"O A p B l the enol acylation subsequent to the alkylation will provide a 3-ester derivative. Accordingly it is apparent that H0 either 6-alkyl-l6-dehydropregnenolone as such or as a 3-ester derivative may be employed as the starting material. From the foregoing reaction scheme it is also apparent that the alkyl groups, R and R may be the same or difierent alkyl groups since they are not introduced simultaneously. The epoxidation also introduces a 5,6-oxido function which on subsequent acid hydrolysis, oxidation of the 3-hydroxyl group and double dehydration affords the 6-methy1-A -dien-3-0ne functionality.

It is, therefore, an object of this invention to provide a novel method of preparation of dialkyl-17-oxygenated progesterones.

It is also an object of this invention to provide novel 6,16-dialkyl steroid compound intermediates which may be converted to the progestationally active 6,16-dialkyl- 17-oxygenated progesterones.

It is further an object of this invention to provide novel 6,.16-dialkyl steroid compounds having the formulae:

0g; /0-Acyl O H; O-Acyl O Hi0 I H10 "0 .R! R! H t) H O l A I acyl-0Q v acyl-O R (cis and trans forms) (cls and trans forms) where R and R'are alkyl groups having from 1 to 8 carbon atoms, A is selected from the group consisting of and R" is selected from the group consisting of hydrogen or acyl groups and B is selected from the group consisting of will be made only to the dimethyl products and to the acetate esters. As has been pointed out, however, other alkyl groups and ester groups may be employed.

(1) ALKYLATION AND ENOL ACYLATION OF 6- METHYL 5,16 PREGNADIEN 3B-OL-20-ONE 3-ACETATE (I) Treatment of the above A -dehydro-20-ketone compound with methyl Grignard reagent produces an intermediate dimethylated Grignard complex which, without isolation, is treated with an acetylating agent. There is thus produced a mixture of the cis and trans forms of 6,l6a-dimethyl-5,l7 (20)-pregnadien-3fi,20-diol 3,20-diacetate (Ila and I111).

The reaction is normally carried out with about 2.4 moles of methyl magnesium bromide per mole of A dehydro--ketone. As little as 1.5 moles per mole of steroid may be employed. Ratios of greater than 2.4 moles per mole of steroid may be used but no increased beneficial eifect is obtained thereby. Other alkyl magnesium bromides may be employed to give other 16- alkylated compounds. Alkyl magnesium iodides and dialkyl magnesium compounds may also be used. The 1,4- addition of the Grignard reagent to the a d-unsaturated ketone system is catalyzed by the addition of cuprous chloride. Normally the salt is added in a ratio of about 0.1 mole per mole of steroid. Lesser ratios are substantially as effective, but larger ratios show no increased beneficial eifect. Other cuprous halides may also be used such as cuprous bromide or cuprous iodide. The solvent mixture normally used is a mixture of ethyl ether and tetrahydrofuran. Dioxane may also be used in place of tetrahydrofuran but the results are less satisfactory.

The reaction is normally carried out under an inert atmosphere such as nitrogen gas for a period of about 45 minutes at about C. Lower temperatures may be employed but then longer reaction times are required. Somewhat higher temperatures and shorter times may also be employed but in these cases some attack of Grignard reagent on the 3-ester function is observed.

After the termination of the Grignard alkylation period, the intermediate Grignard complex is acetylated at about 25 C. by the addition of an acetylating agent. The acetylation agents normally employed are acetyl chloride or acetic anhydride, usually diluted with a solvent such as tetrahydrofuran. Other acylating agents may be used such as propionyl chloride, propionic anhydride and the like. After the acylating agent has been introduced, the mixture is allowed to stir for a period of about 45 minutes at about 25 C.

The reaction mixture is finally treated with saturated aqueous ammonium chloride solution to decompose the excess Grignard reagent. Other ammonium salts may be used and even water alone may be used followed by acidification with, for example, hydrochloric acid. The solvent layer is diluted with ethyl acetate, separated from the aqueous layer, and washed free of inorganic materials. After drying, the solvents are removed in vacuo to give the crude dialkylpregnadiene-d-iol diacylate. This product is a mixture of cis and trans isomeric forms (Ila and 11b). In practice, these isomers are used. without separation. The presence of the desired functionality is indicated by the characteristic infrared spectrum.

(2) EPOXIDATION OF CIS AND TRANS 6,16a-DI- METHYL 5,l7(20) PREGNADIEN-3,8,20-DIOL 3,20-DIACETATE (Ha AND iIb) The pregnadiendiol diacetate is epoxidized by treatment 7 with a peracid to give the corresponding 5,6:l7a,20-di- 6 zene, toluene or the like. The time of the reaction will depend on the peracid used, longer with perbenzoic acid and even longer with monoperphthalic acid at the same temperature.

At the end of the reaction with peracetic acid, which may be followed if desired by ioclometric titration of samples, the reaction mixture is diluted with, for example, methylene chloride, the solvent layer separated and washed thoroughly with aqueous sodium bicarbonate solution and water. After drying, the solvents are removed in vacuo to give the crude mixture of cis-trans and 5,6aand ,8- dioxido compounds (Illa-a). Further reaction is normally carried on without separation. The presence of the desired functional groups is indicated by the characteristic infrared spectrum.

(3) ALKALINE HYDROLYSIS OF THE 5,6:l7u,20-

DIOXIDO 6,160: DlMETHYLPREGNAN-3 3,20 DIOL 3,20-DIACETATES (111a, 1111), HR, AND IIId) Hydrolysis of the 3- and 20-acetate groupings to give the mixture of 5a,6a-oxido-6B,lda-dimethylpregnan-iifi, 17 oc-diOl-ZO-One and 513,6,8-0Xid0-6oc, l Ga-dimethYl-pregnam 3,8,17u-diol-20-one (IVa and IVE) is carried out with potassium carbonate in aqueous methanol. Under these alkaline conditions, the ester functions at 3 and 20 are removed. The intermediate 17u,20-oxido-20-alcohol thus produced is unstable under the hydrolysis conditions and spontaneously rearranges in situ to the l7a-hydroxy-20- ketone system.

This alkaline hydrolysis-rearrangement is normally carried out by treatment with aqueous methanolic potassium carbonate at the reflux temperature of the mixture. Other alkalis and solvent mixtures may be used, however, for example potassium hydroxide in aqueous ethanol, sodium hydroxide in aqueous methanol or ethanol, or s di m carbonate in aqueous ethanol. Using the stronger bases, the required reflux period is shorter. Also with the stronger bases, the reaction may be carried out at room temperature but substantially longer times are required.

The product is normally isolated by acidification with acetic acid, evaporation in vacuo to remove most of the alcohol solvent, and then extraction of the steroidal material with ethyl acetate or other suitable water immiscible solvents such as chloroform, methylene chloride, and the like. For acidification, other water soluble organic acids may be used and even mineral acids such as hydrochloric acid providing no excess is introduced.

The solvent extracts are washed free of acids and inorganic materials and the solvent removed in vacuo to give the mixture of isomeric 5a,6aand 5/3,6,B-oxidodimethylpregnandiolones (IVa and IVb). Separation of the isomeric 5,6-oxides may be accomplished by a fractional crystallization or by column chromatography on' alumina but in practice the mixture of isomers is utilized without separation since they both give the same product in the subsequent step. The characteristic infrared spectrum of the mixture serves to identify the component oxides.

(4) HYDROLYTIC CLEAVAGE OF THE 5,6-OXIDO-- 6,1604 DIMETHYLPREGNAN 313,17a-DIOL-20- ONES (IVa AND IVb) Acid-catalyzed hydrolytic opening of either of the isomeric 5,6-oxides (IVa and IVb) produces the same trans 5a,6B-diol system. Thus both IVa and IVb give 60:,1611- dimethylpregnan-lifi,5a,6 fi,17u-tetrol-20-one.

Normally this acid-catalyzed hydrolysis is carried out in aqueous acetone containing perchloric acid. The ratio of water to acetone is normally about 3:8 but small variations in this ratio have no material elfect in the course of the reaction. The normality of the perchloric acid in the mixture isnormally about 0.3 N, but normalities of 0.1 N or less may be used and also normalities as high as 1.0 N are effective. The rate of hydrolysis is dependent on the acid concentration, being slower with lower concentrations and vice versa. When the perchloric acid concentration is about 0.3 N, the reaction is complete in about 45 minutes at about 25 C. Other strong acids such as sulfuric acid orv periodic acid may also be used. The concentration, time and temperature will depend somewhat on the particular acid used.

At the end of the reaction period, about 10 volumes of water are added and the precipitated steroid extracted with ethyl acetate. Other solvents such as chloroform, methylene chloride and the like may be used. The solvent extracts are washed thoroughly with water, aqueous sodium bicarbonate or the like, again with water and finally dried. Removal of the solvents in vacuo thus affords the crude crystalline dimethylpregnantetrolone (V). The pure material may be obtained by recrystallization from the usual solvents such as, for example, a mixture of acetone and Skellysolve B, essentially an n-hexane hydrocarbon fraction.

OXIDATION OF 60:,16a-DIMETHYLPREGNAN- 313,5a,65,l7a-TETROL-20 ONE v Selective oxidation of the 3fl-alcohol function to the corresponding 3-ketone is normally carried out by treatment of the tetrolone (V) in acetone solution with a solution of chromium trioxide in dilute aqueous sulfuric acid. The reaction is very rapid and is normally complete in about 3 minutes. At the end of this time, the excess chromium trioxide is destroyed and the mixture diluted by the addition of an excess of aqueous sodium sulfite solution. Other ketone solvents, such as methyl ethyl ketone, may be employed providing they are not oxidized themselves. In place of sodium sulfite, other reducing salts such as sodium bisulfite, potassium sulfite and the like may be used. Other oxidizing systems may also be used such as chromium trioxide in acetic acid or chromium trioxide in pyridine.

The product is recovered by extraction with a waterimmiscible solvent such as ethyl acetate. Chloroforni, methylene chloride, and the like may also be used. The solvent extracts are Washed free of inorganic materials and acids with water and aqueous sodium bicarbonate solution then dried and evaporated to dryness in vacuo to give the crude crystalline dimethylpregnanetriol-dione (VI). The pure materialis obtained by crystallization from solvent mixtures such as acetone and Skellysolve B.

(6) DEHYDRATION OF 60,160L-DIMETHYLPREG- NAN-Sondfi,l7a-TRIOL-3-20-DIONE (VI) The 5a,6fl-dihydroxy-3-ketone system of compound VI is converted to the A -diene-3-one system by treatment with an acid in an alcohol solvent. Under these conditions the 5u-hydroxyl and the 6,8-hydroxyl groups are eliminated as water to form the 4,6-diene system in 6,16otdimethyl-4,6-pregnadien-l7ot-ol-3,20-dione (VII) (A -dehydro-6,l6ot-dimethyl-l7a-hydroxy progesterone), which is identical to the material prepared in our copending application Serial No. 88,030, for 17-Oxygenated-6 l6-Dialkyl Progesterones, filed February 9, 1961.

Normally, the dihydroxy ketone (V1) is heated under reflux in ethanol containing a small quantity of concentrated hydrochloric acid for a period of about 40 minutes. Other strong acids may be used such as sulfuric acid, ptoluenesulfonic acid, g,4-dinitrobenzenesulfonic acid, and the like. Other alcoholic solvents may be used such as methanol or isopropanol. The exact times of reflux will depend on the acid strength of the particular acid used and on the boiling point of the mixture.

The product is recovered by concentrating the reaction.

mixture in vacuo at about room temperature to remove 70-80% of the solvent. Dilution with 6-10 volumes of water causes precipitation of the crystalline product which is removed by filtration, thoroughly washed With water and dried in vacuo. Recrystallization from Skellysolve B affords the pure product (VII).

8 (7) ACYLATION OF 6,160t-DIMETHYL-4,6-PREGNA- DIEN-l7aOL3,20-DIONE (VII) The 17a-hydroxyl group of VII is acetylated to form 6,l6ot-dimethyl-4,6-pregnadiene-17a-ol-3,20-dione l7-acetate (VIII), (A -dehydro-6,l6ot-dimethyl-l7a-hydroxyprogesterone acetate) by treatment with acetic anhydride and p-toluenesulfonic acid in glacial acetic acid solution. The reaction is normally carried out at room temperature for periods of 16-72 hours. Other acylating agents may be used such as propionic anhydride, caproic anhydride and the like. When other anhydrides are used to form other acylates, the solvent used must be the acid corresponding to the anhydride. Other acid catalysts such as 2,4-dinitrobenzene sulfonic acid may also be used. The time of the reaction will depend upon the temperature as well as the nature of the reagents and solvents used.

The product is isolated by diluting the reaction mixture with water followed by extraction of the steroid with a solvent such as ethyl acetate, chloroform, methylene chloride or the like. The extracts are Washed free of acids by washing with aqueous sodium bicarbonate, then dried and evaporated to dryness in vacuo. The pure l7-acetate or other acylate may be isolated by crystallization from solvents such as Skellysolve B, or by chromatography on alumina.

The crude 17-acetate or other acylate will sometimes contain small amounts of the corresponding ester of the 3-enol. This enol ester can be selectively hydrolyzed by treatment with a small amount of hydrochloride acid in methanol solution. Under these conditions, the 3-enol ester is selectively hydrolyzed to the original B-ketone function leaving the l7-acetate or other acylate function intact. Other strong acids and other alcoholic solvents may also be employed.

The acidic methanol mixture is diluted with Water to precipitate the desired 17-acetate or other acylate. The product is normally precipitated as a solid and can be removed by filtration. In some instances, the product is not crystalline and is then extracted with a solvent such as ethyl acetate, chloroform, methylene chloride, and the like. Final purification of the 17-acetate or other acylate is accompanied by crystallization from Skellysolve -B or the like.

This prbduct, A -dehydro-6,16e-dimethyl-l7ot-hydroxyprogesterone acetate may be further dehydrogenated to provide the A -bisdehydro derivative by a variety of reactions as disclosed in our copending application Serial No. 88,030 for 17-Oxygenated-6,l6-Dialkyl Progesterones filed on February 9, 1961. As disclosed therein, the A double bond may be introduced into ring A of the nucleus by the use of chloranil in refluxing sec-amyl alcohol. The A -double bhnd may also be introduced selectively by the dehydrogenating action of selenium dioxide, by

T fermentation with. certain species of microorganisms or by treatment with 2,3-dichloro-5,6-dicyanobenzoquinone.

Representative of the starting material is 6-methyl-5 ,16- pregnadien-BB-ol-ZO-one B-acetate shown generically as Formula I in the preceding schematic representation. This starting material may be prepared in accordance with US. Patent No. 2,871,246.

The invention can best be illustrated by means,of the following examples which are intended as illustrative of the process and products of the present invention, but are not to be construed as limiting the invention.

Example I ALKYLATION AND ENOL ACETYLATION OF s-METHYL- n5,16-PREGNADIEN-3B-Olr20-ONE s-AcETAtrE (I) To 50 ml. of dry tetrahydrofuran under nitrogen was added 8 ml. of a 3 M solution of methyl magnesium bromide in ether. After removing 28 ml. of the mixture by distillation and cooling to room temperature, 200 mg. of cuprous chloride was added. With stirring a solution of 3.70 g. of 6-methyl-5,l6-pregnadien 3fl-oI-ZO-one chloride solution, dried, and evaporated in vacuo to an oil which had 2,115.74, 5.90 (shoulder), 8.1-8.2, 8.41 and 8.65

and corresponded to a mixture of cis and trans 6.16adimethyl 5,17(20) pregnadien-3;3,20-diol 3,20-diacetate (11a and Ilb).

Example 11 EPOXIDATION OF CIS AND TRANS 6,16a-DIMETHYL- 5,17(20)- PREGNADIEN 35,20 DEOL 3,20 DIACETATE (IIa AND 111;)

The crude cis and trans 6 ,1'6a-dimethyl-5,17(20)- pregnadien-3fl,20-diol 3,20-diacetate (11a and Ilb), 4.5 g., was dissolved in 30 ml. of chloroform and added to a stirred mixture of 10 ml. of 40% peracetic acid and 1.0 g. of anhydrous sodium acetate. The reaction mixture was stirred for five hours at room temperature, then poured into water and diluted with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate solution, once with water and finally with satunated sodium chloride solution, dried and evaporated to a solid which was a mixture consisting of cisand trans-50 m:17a,20-dioxido-6p,16adimethylpregnan 30,20-diol 3, ZO-diacetates and cisand trans 5 0,6 6: 17 a,20-dioxido 6a,16ot-dimethylpregnan 3 13, ZO-diol 3,20-diacetates (1111a .and 111k, IIIc and IIId) having 5.74, 8.13, 8.60 and 8.88

Example 111 ALKALINE HYDROLYSIS OF THE 5,6:17a,20-DIOXIDO- 6,160. DIMETHYLPREGNAN 35,20 DIOL 3,20 DIACE- TATES (I110, 111b, 1110 AND IIId) The mixture of 5,6 :17,20-diepoxides from Example II (4.9 g.) was taken up in 100 ml. of methanol to which was added a solution of 2.0 g. of potassium carbonate in 25 ml. of water. The mixture was heated under reflux for 45 minutes, then cooled and 2 ml. of glacial acetic acid added. After concentrating the mixture in vacuo to about /5 of the original. volume, 200' ml. of water was added and the resulting precipitate removed by filtration, washed and dr-ied to give 3.2 g. of a mixture of 5a,6a oxide-6,8,16ot-dimethylpregnan-3p,17a-diol-20-one (IVa) and 5,8,6fl-oxido-6u,16ot-dimethylpregnan-3fl,17adiol-20-one (IVb) which had his? 2.90, 5.90 and 11.60;:

Example IV HYDROLYTIC CLEAVAGE OF THE 5,6-OXIDO G,16a-

DIMETHYLPREGNAN-3fi,17a-DIOL-20-ONES (IVa AND IVb) A 3.2 g. sample of the mixed 5a,6otand 55,6;3-ox-ido- 6,16u-dimethylpregnan-3fi,17a-diol 20 ones (IVa and IVb) was dissolved in 80 ml. of acetone. With stirring, 30 ml. of a 1 N aqueous perchloric acid solution was added. After 45 minutes had elapsed, one liter of water was added and the resulting suspension extracted with two 100 m1. portions of ethyl acetate. The extracts were washed with water, once with 5% aqueous sodium bicarbonate solution and finally with saturated sodium chloride solution, dried and evaporated in vacuo to a solid, 6a,16a-dimethyl-pregnan-3fl,50;,60,17a-tetrol-20-one (V), which had a melting point of about 130-135 Recrystallization from acetone-Skellysolve B gave amorphous r 1 0 material changing to a microcrystalline form at 131139 finally melting at 209-2l5, [(11 -10.7 (dioxane),

A535. 2.90, 5.86 and 9.48, Example V OXIDATION OF 611,16a DIMETHYLPREGNAN-3B,541,65- 17a-TETROL-20-ONE (V) To a solution of 6.2 g. of 6u,16a-dimethylpregnan-3fl, 50c,6,6,17m-tetrol-20-one (V) in ml. of acetone was added in 60 seconds, with stirring, 12 ml. of an 8 N chromic acid solution, prepared as follows: 5.34 g. of chromium trioxide was dissolved in a mixture of 20 ml. of water and 4 ml. of concentrated sulfuric acid. After three minutes total elapsed time there !W3.S added a solution of 5 g. of sodium sulfite in 15 ml. of water. Ethyl acetate was added, the organic layer separated and washed with saturated sodium chloride solution, once with 5% aqueous sodium bicarbonate solution, again with saturated sodium chloride solution, dried and evaporated in vacuo to a solid, weight 5.2 g. Recrystallization from acetone-Skellysolve B gave 60:,16a-dimethy1pregnan-5ot, 6B,17ot-triol-3,20-dione (VI) melting at about 225233. Further recrystallization from acetone-Skellysolve B raised the melting point to 231.5234.5, -29 (dioxane),

AKB:

max. max.

and 629,0.

Example VII ACETYLATION OF 6,16a-DIMETHYL4,S-PREGNADIEN- 17a-OL3,20-DIONE (VII) To a solution of 0.38 g. of 6,16u-dimethyl-4,6-pregnadien-17a-ol-3,20-dione (VII) in 20 ml. of glacial acetic :acid was added 2.0 ml. of acetic anhydride followed by 0.15 g. of p-toluenesulfonic acid. After standing for 22 hours at room temperature the mixture was poured into 300 ml. of water. The oil which separated was extracted with ethyl acetate. The extracts were washed with 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated in vacuo to an oil. This oil was taken up in 20 ml. of methanol and 0.2 ml. of concentrated hydrochloric acid added. After standing for 2 hours at room temperature 100 ml. of water was added and the resulting precipitate removed by filtration giving 0.40 g. of 6,16a-dimethyl-4,6-pregnadien-l7u-ol-3,20-dione 17-acetate melting at about 163- 180. Several recrystallizations from Skellysolve B raised the melting point to 189.5-, [a] -[25.6 (chloroform),

0.14, 0.30, 803- and 11.39,.

Example VIII PREPARATION OF A-DEHYDRO6,16a-DIMETHYIr17a- HYDROXYPROGESTERONE CAPROATE max.

and 15 m1. of n-hexanoic anhydride. After flushing with nitrogen, 0.85 g. of p-toluenesulfonic acid monohydrate was added and the mixture stirred for 66 hours at room temperature. Five m1. of pyridine was then added and the mixture steam distilled until no more oily distillate appeared. The suspension of oily product remaining was extracted with ethyl acetate and the extracts were washed as follows: once with dilute hydrochloric acid, once with water, once with aqueous sodium bicarbonate solution and once with saturated sodium chloride solution. After drying, the solvent was evaporated in vacuo to give an oil.

The oil was taken up in 50 ml. of methanol and 0.5 ml. of concentrated hydrochloric acid added. After standing for 2 hours the mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and evaporated in vacuo to an oil which was dissolved in Skellysolve B and placed on 30 g. of alumina. Mixtures of Skellysolve B and benzene eluted the A -dehydro-6,l6adimethyl-17a-hydroxyprogesterone caproate as an oil, 1.16 g. The purified oily caproate was distilled at 0.04 mm. of mercury and 199-204 bath temperature to give a glassy solid, [a] +7.4- (1%, CHCl EtOH A max- ML 290 my (e 22,800),

8.58 and 11.38 m

It is to be understood that the invention is not to be limited to the exact details of operation or the exact compounds shown and described, as obvious modifications and equivalents will be apparent to those skilled in the art and the invention is to be limited only by the scope of the appended claims.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A 6,16-dialkyl steroid compound selected from the group consisting of the cis and trans forms of Where R and R are alkyl groups having from 1 to 8 carbon atoms and R' is an alkyl group having from 1 to 12 carbon atoms.

2. A 6,16-dialkyl steroid compound as defined in claim 1 where R is methyl.

3. A 6,1 6-dialkyl steroid compound as defined in claim .1 where R' is methyl.

4. A 6,16-dia1kyl steroid compound selected from the group consisting of the cis and trans forms of where A is selected from the group consisting of and where A is selected from the group consisting of at I and

and R and R are alkyl groups having from 1 to 8 carbon atoms.

8. A 6,1'6-dialkyl steroid compound as defined in claim 7 wherein R is methyl.

9. A 6,1'6-dialkyl steroid compound as defined in claim 7 wherein R is methyl.

10. A 6,16-dialkyl steroid compound having the formula where R and R are alkyl groups having from 1 to 8 carbon atoms.

11. A 6,16-dialky1 steroid compound as defined in claim 10 wherein R is methyl.

12. A 6,16-dialkyl steroid compound as defined in claim 10 wherein R is methyl.

13. In a process of preparing 6,16-dia1ky1-17-oxygenated-6-dehydro progesterone compounds the sequence of steps comprising (A) alkylating a 6-alkyl-5,l6-pregnadien- 3fl-ol-20-one 3 acylate with an alkyl metal halide, (B) acylating the product of (A), (C) epoxidizing said acylated product with a peracid to provide the 5,6: 17,20- dioxido compound, (D) hydrolyzing said dioxido compound under alkaline conditions to provide the 5,6-oxido- 3,17-01 20-one compounds, (E) hydrolyzing the product of (D) under acid conditions to provide the 5,6-diol, (F oxidizing the 3-hydroxy function to a ketone function, and (G) dehydrating the product of (F) to provide the 6,16- dialkyl-l7-oxygenated-6-dehydro progesterone compound.

14. In a process of preparing 6,16a-dialkyl-4,6-pregnadien-17a-ol-3,20-dione from a 6-alkyl-5,16-pregnadien-313- ol-20-one 3 acylate the step of epox-idizing with a peracid a 6,16ot dialkyl 5,17(20) pregnadien-ElB,20-diol 3,20-diacylate.

15. In a process of preparing a 6,l6ot-dialkyl-4,6-pregnadien-l7a-ol-3,20-dione from a 6-alkyl-5,16-pregnadien- 3fl-o1-20-one 3 acylate the steps of hydrolyzing under alkaline conditions a 5,6: 17a,20-dioxido-6,16a-dialkylpregnan- 313,20-diol 3,20-diacylate and subsequently hydrolyzing the product thereof under acid conditions.

16. A 6,16-dia1kyl steroid compound having the formula Ho OH 16 in which R is methyl.

18. A 6,16-dialky1 steroid compound as defined in claim 20 16 in which R is methyl.

References Cited in the file of this patent UNITED STATES PATENTS Loken Jan. 27, 1959 Kollonitsch et a1 July 5, 1960 

4. A 6,16-DIALKYL STEROID COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE CIS AND TRANS FORMS OF
 13. IN A PROCESS OF PREPARING 6,16-DIALKYL-17-OXYGENATED-6-DEHYDRO PROGESTERONE COMPOUNDS THE SEQUENCE OF STEPS COMPRISING (A) ALKYLATING A 6-ALKYL-5, 16-PREGNADIEN3 B-OL-20-ONE 3 ACYLATE WITH AN ALKYL METAL HALIDE, (B) ACYLATING THE PRODUCT OF (A), (C) EPOXIDIZING SAID ACYLATED PRODUCT WITH A PERACID TO PROVIDE THE 5,6:17,20 DIOXIDO COMPOUND, (D) HYDROLYZING SAID DIOXIDO COMPOUND UNDER ALKALINE CONDITIONS TO PROVIDE THE 5,6-OXIDO3,17-OL 20-ONE COMPOUNDS, (E) HYDROLYZING THE PRODUCT OF (D) UNDER ACID CONDITIONS TO PROVIDE THE 5,6-DIOL, (F; OXIDIZING THE 3-HYDROXY FUNCTION TO A KETONE FUNCTION, AND (G) DEHYDRATING THE PRODUCT OF (F) TO PROVIDE THE 6,16DIALKYL-17-OXYGENATED-6-DEHYDRO PROGESTERONE COMPOUND. 